It has become clear that in many cases, pulmonary immunity is genetically regulated. However, the identification of genetic determinants of pulmonary immune responses has not been elucidated. Our laboratory has described a murine infection model of a fungal pathogen, Cryptococcus neoformans (Cne), in which two genetically distinct inbred strains of mice yield either a Th1 or Th2 adaptive immune response upon infection. Importantly, the genetic determinants of the adaptive immune responses to Cne dictate whether a self-limiting and effective Th1 immune response or an ineffective, chronic Th2 immune response is generated. Using a quantitative trait loci (QTL) approach to identify the genetic determinants regulating the generation of Th1 or Th2 immune responses to Cne infection in mice, we have identified important genetic regions on chromosomes 3 and 6 that regulate the generation of an effective Th1 immune response leading to clearance of Cne from the respiratory tract. Specifically, this application seeks to 1) identify whether the cells orchestrating the genetically distinct immune responses are hematopoietic or somatic in origin; and 2) refine the chromosomal regions in chromosomes 3 and 6 to elucidate gene targets important in regulating the immune response to Cne infection in vivo. The studies proposed in this application will provide novel insights into candidate genes that are involved in the development of either Type 1 or Type 2 pulmonary immunity.